Mechanism of Morinda officinalis iridoid glycosides alleviates bone deterioration in type II collagen-induced arthritic rats through down-regulating GSK-3β to inhibit JAK2/STAT3 and NF-κB signaling pathway
10.16438/j.0513-4870.2024-0189
- VernacularTitle:巴戟天环烯醚萜苷下调GSK-3β抑制JAK2/STAT3和NF-κB通路减轻II型胶原诱导的关节炎大鼠骨破坏的机制
- Author:
Yi SHEN
1
;
Yi-qi SUN
1
;
He-ming LI
1
;
Xin-yuan YE
1
;
Jin-man DU
1
;
Rong-hua BAO
2
;
Quan-long ZHANG
1
;
Lu-ping QIN
1
;
Qiao-yan ZHANG
1
Author Information
1. School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
2. Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou 311400, China
- Publication Type:Research Article
- Keywords:
italic>Morinda officinalis iridoid glycoside;
rheumatoid arthritis;
bone loss;
osteoclast;
NF-κB signaling pathway;
JAK2/STAT3 signaling pathway
- From:
Acta Pharmaceutica Sinica
2024;59(10):2763-2772
- CountryChina
- Language:Chinese
-
Abstract:
This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides (MOIG) on bone loss of rheumatoid arthritis (RA) rats, and the mechanism of osteoclast function and activity induced by lipopolysaccharide (LPS). RA rats were established by injecting bovin type II collagen. The Bio-ethic Committee of Zhejiang Chinese Medical University approved all experimental protocols associated with this study (IACUC-20180410-03). The collagen-induced arthritis (CIA) rats were administered drug by gavage for 8 weeks; the femoral trabecular micro-structure changes were observed in CIA rats by micro-CT; the LPS-induced osteoclasts model further observed the effect and mechanism of anti-inflammatory osteoporosis in vitro. The results indicated that MOIG could markedly increase bone mineral density (BMD) in CIA rats, improve trabecular micro-structure. In vitro studies demonstrated that MOIG could significantly inhibit osteoclastogensis and differentiation, suppress tartrate resistant acid phosphatase (TRAP) activity, F-actin ring formation, TNF receptor associated factor 6 (TRAF6) recruitment, and inhibitor of nuclear factor kappa-Bα (IκBα) degradation as well as p65 phosphorylation, thereby repressing nuclear factor kappa-B (NF-κB) signaling pathway activation. Subsequently, MOIG effectively inhibited osteoclast nuclear factor of activated T-cells c1 (NFATc1) and cellular oncogene Fos (c-Fos) expression, as well as bone resorption related protein activity including matrix metalloprotein 9 (MMP-9) and cathepsin K (CtsK). Meanwhile, MOIG also repressed the phosphorylation expression of Janus activating kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), thereby inhibiting JAK2/STAT3 signaling pathway activation. Moreover, further studies found that MOIG could suppress glycogen synthase kinase-3β (GSK-3β) activity, and GSK-3β gene silencing could markedly inhibit oetsoclast F-actin ring formation as well as the phosphorylation expression of p65 and STAT3. Of note, compared with GSK-3β gene silencing group, there was no significant difference in the group treated with both MOIG with GSK-3β gene silencing simultaneously. Thus, the results suggested that MOIG may inhibit NF-κB signaling pathway and JAK2/STAT3 signaling pathway activation via regulating GSK-3β, thereby alleviating bone destruction in RA.
